Hydrogenation process of oxime derivatives

ABSTRACT

The present invention relates to a novel process for the iridium-catalysed hydrogenation of oximes. The invention also relates to novel iridium catalysts for use in the iridium-catalysed hydrogenation of oximes and to processes of preparation of these catalysts. The invention further relates to the use of the novel iridium catalysts in ionic hydrogenation of other unsaturated substrates.

The present invention relates to a novel process for theiridium-catalysed hydrogenation of oximes. The invention also relates tonovel iridium catalysts for use in the iridium-catalysed hydrogenationof oximes and to processes of preparation of these catalysts. Theinvention further relates to the use of the novel iridium catalysts inionic hydrogenation of other unsaturated substrates.

The reduction of oximes and oxime ethers to the correspondinghydroxylamine derivatives is a useful step in many organic syntheses;

Reduction of oximes and oxime ethers using sodium cyanoborohydride orborane complexes such as borane triethylamine complex are described inWO13/127764. The main disadvantages of the borane reduction methods arethe high cost of the reducing agent, low atom economy of the processresulting in formation of stoichiometric amounts of waste and thetoxicity of cyanoborohydride. In many cases the borane oxime reductionsuffers from over-reduction to the corresponding primary amine (J. Chem.Soc. Perkin Trans. I, 1985, 2039).

WO13/127764 discloses heterogeneous hydrogenation of oximes and oximeethers to hydroxylamines in the presence of a platinum-carbon catalystand a strong acid such as sulphuric or hydrochloric acid. The maindisadvantages of this method are the harsh reaction conditions andlimited scope, for example, other easily reducible functional groups onthe substrate such as nitro- or alkene-groups are not tolerated. In somecases the heterogeneous oxime to hydroxylamine hydrogenation suffersfrom over-reduction to the corresponding primary amine as well ascatalyst poisoning.

Reports on homogeneous hydrogenation of oximes and oxime ethers tohydroxylamines are scarce. The transition-metal-catalysed hydrogenationof oximes is commonly plagued by over-reduction to the correspondingprimary amine and low catalytic efficiency (cobalt catalysis—Bull. Chem.Soc. Jpn. 1963, 36, 763; ruthenium catalysis—Tetrahedron: Asymmetry1992, 3, 1283; rhodium catalysis—J. Chem. Soc. Chem. Commun. 1995, 1767;Org. Lett. 2013, 15, 484; Tetrahedron: Asymmetry 2016, 27, 268; iridiumcatalysis—Synth. Commun. 2001, 31, 2767).

EP1862446 discloses a homogeneous iridium-catalysed hydrogenation ofethyl 3-methoxyiminobutanoate derivatives using a combination ofhydrogen at 60 bar, bis (1,5-cyclooctadiene)iridium(I)tetrafluoroborate, and(R)-1-[(S)-2-diphenylphosphinoferrocenyl] ethyl di-tert-butylphosphine.However, in practice this method is limited in scope to oximes of3-ketoesters. Such substrates tautomerize to 2,3-unsaturated esters andso the described oxime hydrogenation reaction is in fact a carbon-carbondouble bond reduction.

Angew. Chem. Int. Ed. 2014, 53, 13278 and Chem. Eur. J. 2015, 21, 17583disclose a homogenous hydrogenation of oxime derivatives using atris(pentafluorophenyl)borane catalyst, however, this method is limitedto oxime ethers bearing a bulky O-substituent (t-butyl orSi[(CH₃)₂CH]₃), and utilises relatively harsh reaction conditions (5%catalyst, 60-100 bar H₂).

Org. Biomol. Chem, 2013, 11, 6934 and related patent applicationsWO13/153407 and WO13/153408 disclose certain cyclopentadienyl iridiumcatalysts for the reductive amination of ketones and aldehydes via thecorresponding imines. However, the catalysts disclosed have been foundto be inefficient for the reduction of oximes.

We have now found that the reduction of oximes using hydrogen can becarried out under relatively mild conditions through the use of certainselected iridium catalysts.

According to the present invention there is provided a process for thehydrogenation of an oxime of formula (I) to produce a hydroxylamine saltof formula (II) by reacting oxime (I) with hydrogen in the presence ofan iridium catalyst of formula (IIIa) or formula (IIIb) and an acid;

wherein R¹, R² and R³ are each independently hydrogen, C₁-C₈alkyl,C₁-C₈hydroxyalkyl, C₁-C₈cyanoalkyl, C₁-C₆alkoxyC₁-C₈alkyl,di(C₁-C₆alkoxy)C₁-C₈alkyl, C₁-C₈haloalkyl, C₂-C₆alkenyl,C₃-C₈cycloalkyl, phenyl, phenylC₁-C₃alkyl or heteroaryl, and wherein thecycloalkyl and phenyl moieties are each optionally substituted with 1 to5 groups selected from hydroxyl, halogen, C₁-C₆alkyl, C₃-C₈cycloalkyl,C₁-C₆haloalkyl, C₁-C₆alkoxy, phenyl, heteroaryl, C₁-C₆alkoxycarbonyl,acylamino, amido, cyano, nitro and C₂-C₆alkenyl; or

R¹ and R² together with the carbon atom to which they are attached mayform a 4- to 8-membered saturated cycloalkyl or heterocyclyl ring,wherein the heterocyclic moiety is a non-aromatic monocyclic ring whichcomprises 1, 2 or 3 heteroatoms, wherein the heteroatoms areindividually selected from N, O and S.

Preferably, R¹, R² and R³ are each independently hydrogen, C₁-C₄alkyl,C₁-C₄hydroxyalkyl, C₁-C₄cyanoalkyl, C₁-C₃alkoxyC₁-C₄alkyl,di(C₁-C₃alkoxy)C₁-C₄alkyl, C₁-C₄haloalkyl, C₂-C₃alkenyl,C₃-C₆cycloalkyl, phenyl, phenylC₁-C₂alkyl or heteroaryl, and wherein thecycloalkyl and phenyl moieties are each optionally substituted with 1, 2or 3 groups selected from hydroxyl, halogen, C₁-C₃alkyl,C₃-C₆cycloalkyl, C₁-C₃haloalkyl, C₁-C₃alkoxy, phenyl, heteroaryl,C₁-C₃alkoxycarbonyl, acylamino, amido, cyano, nitro and C₂-C₃alkenyl; or

R¹ and R² together with the carbon atom to which they are attached mayform a 4- to 6-membered saturated cycloalkyl or heterocyclyl ring,wherein the heterocyclic moiety is a non-aromatic monocyclic ring whichcomprises 1, 2 or 3 heteroatoms, wherein the heteroatoms areindividually selected from N, O and S.

More preferably, R¹, R² and R³ are each independently hydrogen,C₁-C₄alkyl, C₁-C₄hydroxyalkyl, C₁-C₃alkoxyC₁-C₄alkyl,di(C₁-C₃alkoxy)C₁-C₄alkyl, C₁-C₄haloalkyl, C₂-C₃alkenyl, phenyl andphenylC₁-C₂alkyl, and wherein the phenyl moiety may be optionallysubstituted with 1, 2 or 3 groups selected from halogen, C₁-C₃alkyl,C₁-C₃haloalkyl, C₁-C₃alkoxy, C₁-C₃alkoxycarbonyl, hydroxyl, and nitro,preferably chloro, methyl, methoxy, methoxycarbonyl, and nitro.

In one set of embodiments R¹ represents tert-butyl, methoxycarbonyl,1,1-dimethoxymethyl, cyclopropyl, phenyl or benzyl, wherein the aromaticring of each phenyl or benzyl moiety is optionally substituted with 1,2, or 3 groups independently selected from chloro, methyl, methoxy,methoxycarbonyl and nitro;

R² represents hydrogen, methyl or ethyl; and

R³ represents hydrogen, methyl, ethyl, isopropyl, t-butyl, allyl orbenzyl.

In another set of embodiments R¹ represents tert-butyl, methoxycarbonyl,1,1-dimethoxymethyl, cyclopropyl, 2-methylphenyl, 2-chlorophenyl,4-nitrophenyl, 4-methoxyphenyl, 2-bromobenzyl, 4-methoxybenzyl, or2,4,6-trichlorobenzyl;

R² represents hydrogen, methyl or ethyl; and

R³ represents hydrogen, methyl, ethyl, isopropyl, t-butyl, allyl orbenzyl.

In one set of embodiments R¹ represents phenyl or benzyl, wherein thearomatic ring of each phenyl or benzyl moiety is optionally substitutedwith 1, 2, or 3 groups independently selected from chloro, methyl,methoxy, methoxycarbonyl or nitro;

R² represents hydrogen or methyl; and

R³ represents hydrogen, methyl, ethyl, isopropyl, t-butyl, allyl orbenzyl.

In a most preferred embodiment, the hydroxylamine of formula (II) isN-methoxy-1-(2,4,6-trichlorophenyl)propan-2-amine (II-1).

R⁶, R⁷, R⁸, R⁹ and R¹⁰ are each independently hydrogen or C₁-C₃alkyl.Preferably, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are each independently hydrogen ormethyl, more preferably, R⁶, R⁷, R⁸, R⁹ and R¹⁰ each represent methyl.

Represents a bidentate chelating ligand comprising at least one carbonatom which coordinates to iridium and at least one nitrogen atom whichcoordinates to iridium. Many metal-chelating ligands are known to thoseskilled in the art, and will be suitable for use in the presentinvention. Particularly suitable bidentate chelating ligands are thosewith a 1,4-relationship between the coordinating nitrogen and carbonatoms, preferably, those where the coordinating carbon atom forms partof a phenyl ring, wherein said phenyl ring is substituted in the orthoposition.

Preferred bidentate chelating C,N ligands are ligands of structure (IV),(IVa) or (IVb):

wherein R^(11A), R^(11B), R^(11C), R^(11D), R^(11E), R^(13A), R^(13B),R^(13C), and R^(13D) are each independently hydrogen, halogen,C₁-C₈alkyl, C₁-C₈alkoxy, C₁-C₈haloalkyl, C₁-C₈haloalkoxy,hydroxyC₁-C₈alkoxy, C₁-C₈alkoxyC₁-C₆alkoxy, C₁-C₈alkoxycarbonyl,C₁-C₈alkoxycarbonylC₁-C₆alkoxy, C₁-C₈alkylcarbonylC₁-C₆alkoxy, phenoxy,or nitro;

R¹² is hydrogen, C₁-C₈alkyl or phenyl; and wherein each phenyl moiety isoptionally substituted by 1 to 5 groups selected from C₁-C₈alkyl andC₁-C₈alkoxy; or

wherein the bidentate chelating ligand is (IVa) or (IVb), R^(11A) andR^(13D) together with the carbon atoms to which they are attached mayform a 5- or 6-membered unsaturated ring, preferably R^(11A) and R^(13D)together with the carbon atoms to which they are attached may form a6-membered unsaturated ring; or

R¹² and R^(13D) together with the carbon atoms to which they areattached may form a 5- to 8-membered partially saturated or unsaturatedcycloalkyl or heterocyclyl ring, wherein the heterocyclic moiety is anon-aromatic ring which comprises 1 or 2 heteroatoms, and wherein theheteroatoms are independently selected from N, O and S. In oneembodiment, R¹² and R^(13D) together with the carbon atoms to which theyare attached may form a 6- to 8-membered partially saturated orunsaturated cycloalkyl or heterocyclyl ring, wherein the heterocyclicmoiety is a non-aromatic ring which comprises 1 or 2 heteroatoms,wherein the heteroatoms are independently selected from N, O and S.

Preferably, R^(11A), R^(11B), R^(11C), R^(11D), R^(11E), R^(13A),R^(13B), R^(13C), and R^(13D) are each independently hydrogen, halogen,C₁-C₃alkoxy, hydroxyC₁-C₃alkoxy, C₁-C₃alkoxyC₁-C₃alkoxy,C₁-C₃alkoxycarbonylC₁-C₃alkoxy, C₁-C₃alkyl, C₁-C₃alkoxy or nitro, andR¹² is hydrogen, C₁-C₃alkyl or phenyl; and wherein each phenyl moiety isoptionally substituted by 1 to 3 groups selected from C₁-C₃alkyl andC₁-C₃alkoxy; more preferably, R^(11A), R^(11B), R^(11C), R^(11D),R^(11E), R^(13A), R^(13B), R^(13C), and R^(13D) are each independentlyhydrogen, halogen, C₁-C₃alkoxy, hydroxyC₁-C₃alkoxy,C₁-C₃alkoxyC₁-C₃alkoxy, or C₁-C₃alkoxycarbonylC₁-C₃alkoxy, and R¹² ishydrogen, C₁-C₃alkyl or phenyl; and wherein each phenyl moiety isoptionally substituted by 1 to 3 groups selected from C₁-C₃alkyl andC₁-C₃alkoxy; or

wherein the bidentate chelating ligand is (IVa) or (IVb), R^(11A) andR^(13D) together with the carbon atoms to which they are attached mayform a 5- or 6-membered, preferably a 6-membered unsaturated ring; or

R¹² and R^(13D) together with the carbon atom to which they are attachedmay form a 5- to 7-membered, preferably a 6- or 7-membered, partiallysaturated cycloalkyl or heterocyclyl ring, wherein the heterocyclicmoiety is a non-aromatic ring which comprises one O atom. In oneembodiment R¹² and R^(13D) together with the carbon atom to which theyare attached may form a 5- or 6-membered partially saturated cycloalkylor heterocyclyl ring, wherein the heterocyclic moiety is a non-aromaticring which comprises one O atom.

More preferably, R^(11A), R^(11B), R^(11C), R^(11D), R^(11E), R^(13A),R^(13B), R^(13C), and R^(13D) are each independently hydrogen, methyl,methoxy, ethoxy, 2-hydroxyethoxy, 2-methoxyethoxy,methoxycarbonyl-methoxy, iso-propoxycarbonyl-methoxy, or nitro, and R¹²is hydrogen, methyl or phenyl; and wherein each phenyl moiety isoptionally substituted by a single methoxy group; more preferably,R^(11A), R^(11B), R^(11C), R^(11D), R^(11E), R^(13A), R^(13B), R^(13C),and R^(13D) are each independently hydrogen, methyl, methoxy, ethoxy,2-hydroxyethoxy, 2-methoxyethoxy, methoxycarbonyl-methoxy, oriso-propoxycarbonyl-methoxy, or R¹² and R^(13D) together with the carbonatom to which they are attached may form a 6- or 7-membered partiallysaturated cycloalkyl or heterocyclyl ring, wherein the heterocyclicmoiety is a non-aromatic ring which comprises one oxygen atom.

In one embodiment, R^(11A), R^(11B), R^(11C), R^(11D), R^(11E), R^(13A),R^(13B), R^(13C), and R^(13D) are each independently hydrogen,C₁-C₈alkyl, C₁-C₈alkoxy, or nitro.

Examples of bidentate chelating ligands are compounds of formulas(IV-1), (IV-2), (IV-3), (IV-5), (IV-6), (IV-7), (IV-8), (IV-9), (IV-10),(IV-11), or (IV-12) as shown below:

X represents an anionic group, that is, a group with a net negativecharge, and wherein X is not a halogen. In complexes (IIIa) wherein X isa halogen, we have found that the anionic group is too tightly bound tothe metal and such complex doesn't give sufficient amount of thecatalytically active hydride intermediate under neutral or acidichydrogenation conditions. Examples of suitable anionic groups X includethe anionic ligands of the formula R¹⁴—SO₂O— or R¹⁵—C(O)O—, wherein

R¹⁴ is halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl, orphenyl, wherein the phenyl moieties are optionally substituted by 1, 2,3 or 4 substituents, which may be the same or different, selected fromR¹⁶;

R¹⁶ is C₁₋₄alkyl, C₁₋₄haloalkyl, nitro, or halogen, preferably methyl,ethyl, trifluoromethyl, nitro or halogen, more preferably methyl orhalogen, even more preferably methyl, chloro or fluoro.

Preferably, R¹⁴ is hydroxy, methyl, trifluoromethyl, phenyl or tolyl.

R¹⁵ is C₁₋₆haloalkyl or phenyl, wherein the phenyl moieties areoptionally substituted by 1, 2, 3 or 4 substituents, which may be thesame or different, selected from R¹⁷.

R¹⁷ is C₁₋₄alkyl, C₁₋₄haloalkyl, nitro or halogen.

Preferably, R¹⁵ is trifluoromethyl.

In one embodiment, X represents a group of the formula R¹⁴—SO₂O. In oneembodiment, X is mesylate, tosylate, nosylate, sulfate, hydrogensulfate,triflate or trifluoroacetate.

Y represents a neutral ligand, that is, a ligand without an overallcharge. Examples of neutral ligands include, but are not limited to H₂O,alcohols, ethers, ketones, esters, amides and nitriles. Preferably, Y isH₂O, PhCN or MeCN, more preferably, H₂O or MeCN, and most preferably Yis H₂O.

Z represents an anionic group, that is, a group with a net negativecharge, and wherein Z is not a halogen. Examples of anionic groupsinclude ligands of the formula R¹⁴—SO₂O⁻ (wherein R¹⁴ is describedabove), tetrafluoroborate, hexafluorophosphate, perchlorate,tetraphenylborate, tetrakis(3,5-bis(trifluoromethyl)phenyl)borate,tetrakis(pentafluorophenyl)borate, fluorinated alkoxyaluminates,mesylate, triflate, tosylate, nitrate, hydrogenosulfate or sulfate, andother weakly coordinating anionic groups. Preferably, Z is of theformula R¹⁴—SO₂O⁻ (wherein R¹⁴ is described above), mesylate, sulfate,hydrogenosulfate, tetrafluoroborate, hexafluorophosphate,tetraphenylborate, or tetrakis(3,5-bis(trifluoromethyl)phenyl)borate,more preferably, mesylate or tetrafluoroborate.

There is also provided a process in which theN-methoxy-1-(2,4,6-trichlorophenyl)propan-2-amine (II-1) as produced bythe above process is further reacted with3-(difluoromethyl)-1-methyl-pyrazole-4-carbonyl chloride (XII) toprovide3-(difluoromethyl)-N-methoxy-1-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)ethyl]pyrazole-4-carboxamide(XIII):

In one embodiment of the invention, the iridium catalyst is a compoundof formula (III-1), (III-11), (III-17), (III-18), or (III-19),preferably the iridium catalyst is a compound of formula (III-1), thereis also provided a compound of formula (III-1), (III-11), (NI-17),(III-18), or (III-19), preferably there is provided a compound offormula (III-1):

In another embodiment of the invention, there is provided a compound offormula (IIIc) or (IIId):

wherein R⁶, R⁷, R⁸, R⁹ and R¹⁰ are each independently hydrogen orC₁-C₃alkyl. Preferably, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are each independentlyhydrogen or methyl, more preferably, R⁶, R⁷, R⁸, R⁹ and R¹⁰ eachrepresent methyl;

wherein R^(11A), R^(11B), R^(11C), R^(11D), R^(11E), R^(13A), R^(13B),R^(13C), and R^(13D) are each independently hydrogen, halogen,C₁-C₈alkyl, C₁-C₈alkoxy, C₁-C₈haloalkyl, C₁-C₈haloalkoxy,hydroxyC₁-C₈alkoxy, C₁-C₆alkoxyC₁-C₆alkoxy, C₁-C₈alkoxycarbonyl,C₁-C₈alkoxycarbonylC₁-C₆alkoxy, C₁-C₈alkylcarbonylC₁-C₆alkoxy, phenoxy,or nitro;

R¹² is hydrogen, C₁-C₈alkyl or phenyl; and wherein each phenyl moiety isoptionally substituted by 1 to 5 groups selected from C₁-C₈alkyl andC₁-C₈alkoxy; or

R¹² and R^(13D) together with the carbon atoms to which they areattached may form a 5- to 8-membered partially saturated or unsaturatedcycloalkyl or heterocyclyl ring, wherein the heterocyclic moiety is anon-aromatic ring which comprises 1 or 2 heteroatoms, and wherein theheteroatoms are independently selected from N, O and S. In oneembodiment, R¹² and R^(13D) together with the carbon atoms to which theyare attached may form a 6- to 8-membered partially saturated orunsaturated cycloalkyl or heterocyclyl ring, wherein the heterocyclicmoiety is a non-aromatic ring which comprises 1 or 2 heteroatoms,wherein the heteroatoms are independently selected from N, O and S;

X is mesylate, tosylate, nosylate, sulfate, hydrogensulfate, triflate,or trifluoroacetate;

Y is H₂O, PhCN or MeCN; and

Z is mesylate, tosylate, nosylate, sulfate, hydrogenosulfate, triflate,tetrafluoroborate, hexafluorophosphate, tetraphenylborate ortetrakis(3,5-bis(trifluoromethyl)phenyl)borate.

Preferably, R^(11A), R^(11B), R^(11C), R^(11D), R^(11E), R^(13A),R^(13B), R^(13C), and R^(13D) are each independently hydrogen, halogen,C₁-C₃alkoxy, hydroxyC₁-C₃alkoxy, C₁-C₃alkoxyC₁-C₃alkoxy,C₁-C₃alkoxycarbonylC₁-C₃alkoxy, C₁-C₃alkyl, C₁-C₃alkoxy or nitro, andR¹² is hydrogen, C₁-C₃alkyl or phenyl; and wherein each phenyl moiety isoptionally substituted by 1 to 3 groups selected from C₁-C₃alkyl andC₁-C₃alkoxy; more preferably, R^(11A), R^(11B), R^(11C), R^(11D),R^(11E), R^(13A), R^(13B), R^(13C), and R^(13D) are each independentlyhydrogen, halogen, C₁-C₃alkoxy, hydroxyC₁-C₃alkoxy,C₁-C₃alkoxyC₁-C₃alkoxy, or C₁-C₃alkoxycarbonylC₁-C₃alkoxy, and R¹² ishydrogen, C₁-C₃alkyl or phenyl; and wherein each phenyl moiety isoptionally substituted by 1 to 3 groups selected from C₁-C₃alkyl andC₁-C₃alkoxy; or

R¹² and R^(13D) together with the carbon atom to which they are attachedmay form a 5- to 7-membered, preferably a 6- or 7-membered partiallysaturated cycloalkyl or heterocyclyl ring, wherein the heterocyclicmoiety is a non-aromatic ring which comprises one O atom. In oneembodiment R¹² and R^(13D) together with the carbon atom to which theyare attached may form a 5- or 6-membered partially saturated cycloalkylor heterocyclyl ring, wherein the heterocyclic moiety is a non-aromaticring which comprises one O atom.

More preferably, R^(11A), R^(11B), R^(11C), R^(11D), R^(11E), R^(13A),R^(13B), R^(13C), and R^(13D) are each independently hydrogen, methyl,methoxy, ethoxy, 2-hydroxyethoxy, 2-methoxyethoxy,methoxycarbonyl-methoxy, iso-propoxycarbonyl-methoxy, or nitro, and R¹²is hydrogen, methyl or phenyl; and wherein each phenyl moiety isoptionally substituted by a single methoxy group; more preferably,R^(11A), R^(11B), R^(11C), R^(11D), R^(11E), R^(13A), R^(13B), R^(13C),and R^(13D) are each independently hydrogen, methyl, methoxy, ethoxy,2-hydroxyethoxy, 2-methoxyethoxy, methoxycarbonyl-methoxy, oriso-propoxycarbonyl-methoxy; or

R¹² and R^(13D) together with the carbon atom to which they are attachedmay form a 6- or 7-membered, preferably a 6-membered, partiallysaturated cycloalkyl or heterocyclyl ring, wherein the heterocyclicmoiety is a non-aromatic ring which comprises one O atom.

As used herein, the term “halogen” or “halo” refers to fluorine(fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo),preferably fluorine, chlorine or bromine. Most preferably halogen ischlorine.

As used herein, cyano means a —CN group.

As used herein, the term “hydroxyl” or “hydroxy” means an —OH group.

As used herein, amino means an —NH₂ group.

As used herein, acylamino means an —NH(C═O)R_(a) group, where R_(a) is aC₁-C₄alkyl radical as generally defined below.

As used herein, amido means an —(C═O)NR_(a)R_(a) group, where R_(a) isindependently selected from hydrogen or a C₁-C₄alkyl radical asgenerally defined below.

As used herein, nitro means an —NO₂ group.

As used herein, the term “C₁-C₈alkyl” refers to a straight or branchedhydrocarbon chain radical consisting solely of carbon and hydrogenatoms, containing no unsaturation, having from one to six carbon atoms,and which is attached to the rest of the molecule by a single bond.C₁-C₆alkyl, C₁-C₄alkyl, C₁-C₃alkyl and C₁-C₂alkyl are to be construedaccordingly. Examples of C₁₋₈alkyl include, but are not limited to,methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, and1-dimethylethyl (t-butyl). A “C₁-C₂alkylene” group refers to thecorresponding definition of C₁-C₂alkyl, except that such radical isattached to the rest of the molecule by two single bonds. Examples ofC₁-C₂alkylene, are —CH₂— and —CH₂CH₂—.

As used herein, the term “C₂-C₆alkenyl” refers to a straight or branchedhydrocarbon chain radical group consisting solely of carbon and hydrogenatoms, containing at least one double bond that can be of either the(E)- or (Z)-configuration, having from two to six carbon atoms, which isattached to the rest of the molecule by a single bond. Examples ofC₂-C₆alkenyl include, but are not limited to, ethenyl (vinyl),prop-1-enyl, prop-2-enyl (allyl), and but-1-enyl.

As used herein, the term “C₁-C₈alkoxy” refers to a radical of theformula —OR_(a) where R_(a) is a C₁₋₈alkyl radical as generally definedabove. The terms C₁-C₆alkoxy, C₁-C₄alkoxy, C₁-C₃alkoxy and C₁-C₂alkoxyare to be construed accordingly. Examples of C₁₋₆alkoxy include, but arenot limited to, methoxy, ethoxy, propoxy, isopropoxy, and f-butoxy.

As used herein, the term “C₁-C₈haloalkyl” refers to a C₁-C₈alkyl radicalas generally defined above substituted by one or more of the same ordifferent halogen atoms. Examples of C₁-C₈haloalkyl include, but are notlimited to fluoromethyl, fluoroethyl, difluoromethyl, trifluoromethyl,2,2,2-trifluoroethyl, and 3,3,3-trifluoropropyl.

As used herein, the term “C₁-C₈haloalkoxy” refers to a C₁-C₈alkoxyradical as generally defined above substituted by one or more of thesame or different halogen atoms.

As used herein, the term “hydroxyC₁-C₈alkyl” refers to a C₁-C₈alkyleneradical as generally defined above substituted by one or more hydroxygroups as defined above.

As used herein, the term “hydroxyC₁-C₈alkoxy” refers to a C₁-C₈alkoxyradical as generally defined above substituted by one or more hydroxygroups as defined above.

As used herein, the term “cyanoC₁-C₈alkyl” refers to a C₁-C₈alkyleneradical as generally defined above substituted by one or more cyanogroups as defined above.

As used herein, the term “C₁-C₈alkoxyC₁-C₆alkoxy” refers to a radical ofthe formula R_(b)O—R_(a)O— where R_(b) is a C₁-C₈alkyl radical asgenerally defined above, and R_(a) is a C₁-C₆alkylene radical asgenerally defined above. Examples of C₁-C₈alkoxyC₁-C₆alkoxy include, butare not limited to, methoxymethoxy, ethoxymethoxy, and methoxyethoxy.

As used herein, the term “C₁-C₈alkoxycarbonyl” refers to a radical ofthe formula R_(a)OC(O)—, where R_(a) is a C₁-C₈alkyl radical asgenerally defined above.

As used herein, the term “C₁-C₆alkoxyC₁-C₈alkyl” refers to a radical ofthe formula R_(a)OR_(b)—, wherein each R_(a) is independently aC₁-C₆alkyl radical as generally defined above, and R_(b) is aC₁-C₆alkylene radical as generally defined above.

As used herein, the term “di(C₁-C₆alkoxy)C₁-C₈alkyl” refers to a radicalof the formula (R_(a)O)₂R_(b)—, wherein each R_(a) is independently aC₁-C₆alkyl radical as generally defined above, and R_(b) is aC₁-C₆alkylene radical as generally defined above.

As used herein, the term “C₁-C₈alkoxycarbonylC₁-C₆alkoxy” refers to aradical of the formula R_(a)OC(O)R_(b)O—, wherein R_(a) is a C₁-C₈alkylradical as generally defined above, and R_(b) is a C₁-C₆alkyl radical asgenerally defined above.

As used herein, the term “C₁-C₈alkylcarbonylC₁-C₆alkoxy” refers to aradical of the formula R_(a)C(O)R_(b)O—, wherein R_(a) is a C₁-C₈alkylradical as generally defined above, and R_(b) is a C₁-C₆alkyl radical asgenerally defined above.

As used herein, the term “C₃-C₈cycloalkyl” refers to a monocyclic ringradical which is saturated or partially unsaturated and contains 3 to 8carbon atoms. C₃-C₆cycloalkyl and C₃-C₅cycloalkyl are to be construedaccordingly. Examples of C₃-C₈cycloalkyl include, but are not limited tocyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl,cyclopenten-3-yl, and cyclohexen-3-yl.

As used herein, the term “phenylC₁-C₃alkyl” refers to a phenyl ringattached to the rest of the molecule by a C₁-C₃alkyl radical as definedabove. Examples of phenylC₁-C₃alkyl include, but are not limited to,benzyl.

As used herein, the term “heteroaryl” generally refers to a 5- or6-membered monocyclic aromatic ring radical which comprises 1 or 2heteroatoms individually selected from nitrogen, oxygen and sulfur. Theheteroaryl radical may be bonded to the rest of the molecule via acarbon atom or heteroatom. Examples of heteroaryl include but are notlimited to, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl,oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyrimidyl, and pyridyl.

As used herein, ═O means an oxo group, e.g., as found in a carbonyl(—C(═O)—) group.

As used herein, O-mesyl or mesylate refers to a radical of the formula—OS(O)₂CH₃.

As used herein, O-tosyl or tosylate refers to a radical of the formula—OS(O)₂C₆H₄-p-CH₃.

As used herein, O-nosyl or nosylate refers to a radical of the formula—OS(O)₂C₆H₄-p-NO₂.

As used herein, O-triflyl or triflate refers to a radical of the formula—OS(O)₂CF₃.

As used herein, O-trifluoroacetyl or trifluoroacetate refers to aradical of the formula —OC(O)CF₃.

As used herein, tetrafluoroborate refers to a radical of the formula BF₄⁻.

As used herein, tetraphenylborate refers to a radical of the formulaB(C₆H₅)₄ ⁻.

As used herein, tetrakis(3,5-bis(trifluoromethyl)phenyl)boryl refers toa radical of the formula B(3,5-(CF₃)₂C₆H₃)₄ ⁻.

As used herein, hexafluorophosphate refers to a radical of the formulaPF₆ ⁻.

As used herein, sulfate refers to a radical of the formula SO₄ ²⁻.

As used herein, hydrogensulfate refers to a radical of the formula HSO₄⁻.

Some hydroxylamines and hydroxylamine salts of general formula (II) areknown to be intermediates of pesticidally active compounds as describedin WO10/063700.

Suitable iridium catalysts (IIIa) may be prepared via halogen exchangefrom known cyclometalated chloro complexes (VI) Org. Biomol. Chem.,2013, 11, 6934; WO 2013/153407 using a suitable metal salt (X-M, whereinX is as defined in (IIIa), and M represents a metal), such as silvermesylate, silver sulfate, silver p-toluenesulfonate. Alternatively,iridium catalysts (IIIa) may be prepared via cyclometallation of iridiumcomplexes (VII) (wherein X is as defined in (IIIa)) and a suitable C,Nligand for example N,1-bis(4-methoxyphenyl)ethanimine. Such reactionsare preferably done in non-coordinating or weakly coordinating solventsuch as dichloromethane, chloroform, 1,2-dichloroethaneortetrahydrofuran.

If the catalyst synthesis is carried out in the presence of acoordinating solvent such as a nitrile or water then complexes ofstructure (IIIb) (Y and Z are as defined above) may be isolated instead.

According to the process of the present invention, the amount of theiridium catalyst is usually between 0.001 mol % and 5 mol %, preferablybetween 0.01 mol % and 1 mol % based on moles of oxime substrate.

According to the process of the present invention, the hydrogen pressureis usually between 1 and 100 bar, preferably between 5 and 80 bar, morepreferably between 7 and 60 bar, and most preferably between 10 and 50bar.

According to the process of the present invention, the reactiontemperature is usually between −20° C. and 120° C., preferably between0° C. and 100° C., more preferably between 0° C. and 80° C., and evenmore preferably between 10° C. and 60° C.

The oxime hydrogenation is preferably carried out in the presence of atleast a stoichiometric amount of acid. Accordingly the molar amount ofthe acid should be the same or higher than the amount of oxime substrateto be reduced, for example at least from 1 to 3 molar equivalents,preferably from 1 to 2 molar equivalents, and in particular 1, 1.1 or 2molar equivalents. The pKa of the acid has to be such that it can atleast partly protonate the oxime substrate and the hydroxylamineproduct. Accordingly, the pKa of the acid is preferably lower than thepKa of the product hydroxylamine salt (II). Suitable acids for mostoxime substrates include, but are not limited to methanesulfonic acid,p-toluenesulfonic acid, camphorsulfonic acid, sulfuric acid,trifluoroacetic acid and triflic acid, preferably, methanesulfonic acid,p-toluenesulfonic acid, camphorsulfonic acid, sulfuric acid, and triflicacid. More preferably, the acid is selected from methanesulfonic acid,camphorsulfonic acid and sulfuric acid.

Typically the oxime hydrogenation reaction is carried out in thepresence of a solvent, preferred solvents are organic solvents such asalcohols, esters, ethers or hydrocarbons. Preferred solvents arealcohols such as methanol, ethanol, isopropanol, 2-methyl-2-butanol and2-butanol and ethers such as tetrahydrofuran, 1,2-dimethoxyethane andmethyltetrahydrofuran. Most preferred solvents are secondary alcoholssuch as isopropanol and 2-butanol and ethers such as tetrahydrofuran andmethyltetrahydrofuran. Preferably, the solvent is isopropanol.

The present invention also relates to a process for ionic hydrogenationof other unsaturated substrates, for example, acylenamines, imines,enamines, heterocycles, aldehydes and ketones with hydrogen in thepresence of an iridium catalyst of formula (IIIa) or formula (IIIb) andoptionally an acid.

EXAMPLES

The Examples which follow serve to illustrate the invention.

The following abbreviations are used: s=singlet; bs=broad singlet;d=doublet; br d=broad doublet; dd=double doublet; dt=double triplet;t=triplet, tt=triple triplet, q=quartet, sept=septet; m=multiplet;RT=room temperature, Rt=retention time, MH⁺=molecular mass of themolecular cation; DCM=dichloromethane.

¹H and ¹⁹F NMR spectra were recorded on a Bruker Avance III 400spectrometer equipped with a BBFOplus probe at 400 MHz/376.6 MHz,respectively.

The following starting materials are commercially available:

Chloro(pentamethylcyclopentadienyl)[(2-pyridinyl-κN)phenyl-κC]iridium(III)(CAS=945491-51-0);

Chloro(pentamethylcyclopentadienyl){5-nitro-2-{1-[(4-methoxyphenyl)imino-κN]ethyl}phenyl-κC}iridium(III)(CAS=1439402-25-1);

7-(2-methoxyethoxy)tetralin-1-one (CAS=1697644-15-7);

methyl 2-(4-oxotetralin-6-yl)oxyacetate (CAS=1937197-95-9);

7-(2-hydroxyethoxy)tetralin-1-one (CAS=1260011-13-9).

Following starting materials were prepared according literatureprocedures:

Iridium,chloro[5-(ethylmethylamino)-2-(2-pyridinyl-κN)phenyl-κC][(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl](CAS=1379114-67-6), according to Chem. Eur. J. 2012, 18, 6063-6078.

Iridium,chloro[4,5-dimethoxy-2-[1-[(4-methoxyphenyl)imino-κN]ethyl]phenyl-κC][(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl](CAS=1507388-46-6), according to Chem. Eur. J. 2014, 20, 245-252.

Iridium,chloro[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl][5,6,7,8-tetrahydro-3-methoxy-8-[(4-methoxyphenyl)imino-κN]-1-naphthalenyl-κC](CAS=1469468-10-7), according to SYNLETT 2014, 25, 81-84.

Iridium,chloro[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl][5,6,7,8-tetrahydro-8-[(4-methoxyphenyl)imino-κN]-1-naphthalenyl-κC](CAS=1469468-08-3), according to SYNLETT 2014, 25, 81-84.

Iridium,chloro[4,5-dimethoxy-2-[1-[(4-methoxyphenyl)imino-κN]ethyl]phenyl-κC][(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl](CAS=1507388-46-6), according to Chem. Eur. J. 2014, 20, 245-252.

Iridium(2+),triaqua[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]-,sulfate (CAS=254734-81-1), according to WO 2008/093668.

General Procedure 1: Synthesis of N-Aryl Ketimine Ligands of Formula(IV)

The corresponding ketone (1.0 eq.), 4-methoxyaniline (1.1 eq.) andtriethylamine (6.0 eq.) and DCM (0.4M) were charged in a dry reactionflask. Titanium tetrachloride (0.6 eq.) solution in DCM (to make thereaction 0.2M overall) was added dropwise at −78° C. The reactionmixture was stirred for 2-80 h. The reaction mixture was quenched withsat. Na₂CO₃ solution and the mixture was filtered through a bed ofcelite. The aqueous layer was extracted with DCM, the organic layersdried with Na₂SO₄, filtered and concentrated in vacuum to give a crudeproduct. The crude product was either purified by (a) crystallizationwith Et₂O or cyclohexane, (b) column chromatography or (c) used ascrude.

TABLE 1 Ligands prepared according to General Procedure 1: Cpd No.Structure Comments (IV-7)

(E)-7-(2-methoxyethoxy)-N-(4-methoxy- phenyl)tetralin-1-imine 51% yield(the crude product purified by column chromatography - silica, ethylacetate/ cyclohexsane/triethylamine) ¹H NMR (CDCl₃): δ 7.87 (d, J = 2.94Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.03 (dd, J = 2.57 Hz, 8.44 Hz, 1H),6.92 (m, 2H), 6.77 (m, 2H), 4.22 (m, 2H), 3.84 (s, 3H), 3.78 (m, 2H),3.47 (s, 3H), 2.84 (t, J = 5.87, 2H), 2.54 (t, J = 6.24, 2H), 1.90 (m,2H) ppm. ¹³C NMR (CDCl₃): δ 165.8, 157.4, 155.8, 144.7, 134.9, 134.1,129.8, 120.8, 119.6, 114.3, 109.2, 71.1, 67.4, 59.2, 55.5, 29.7, 29.2,23.3 ppm. (IV-8)

methyl 2-[(4E)-4-(4-methoxyphenyl)imino- tetralin-6-yl]oxyacetate 60%yield (crude product 85% NMR purity was used in the next step withoutfurther purification) ¹H NMR (CDCl₃): δ 7.83 (d, J = 2.9 Hz, 1H), 7.15(d, J = 8.4 Hz, 1H), 7.05 (dd, J = 8.1, 2.6 Hz, 1H) 6.95-6.91 (m, 2H),6.79-6.75 (m, 2H), 4.73 (s, 2H), 3.84 (s, 3H), 3.82 (s, 3H), 2.88- 2.82(m, 2H), 2.54 (m, 2H), 1.93-1.85 (m, 2H) ppm. (IV-9)

2-[(4E)-4-(4-methoxyphenyl)iminotetralin-6- yl]oxyethanol 14% yield (thecrude product was purified by column chromatography - silica, ethylacetate/ cyclohexane/triethylamine) ¹H NMR (CDCl₃): δ 7.87 (d, J = 2.9Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 7.00 (dd, J = 8.4 Hz, J = 2.9 Hz, 1H)6.95-6.90 (m, 2H), 6.80-6.75 (m, 2H), 4.20-4-16 (m, 2H), 4.00-3.95 (m,2H), 3.84 (s, 3H), 2.85 (t, J = 6.2 Hz, 2H), 2.55 (t, J = 6.2 Hz, 2H),1.95-1.85 (m, 2H) ppm. ¹³C NMR (CDCl₃): δ 165.9, 157.2, 155.9, 144.6,135.0, 134.3, 129.9, 120.9, 119.2, 114.3, 109.6, 69.4, 61.5, 55.5, 29.7,29.2, 26.9, 23.3 ppm.

General Procedure 2: Synthesis of Iridium-Chloro-Complexes of Formula(VI)

Dichloro(pentamethylcyclopentadienyl)iridium(III)dimer (1.0 eq.), sodiumacetate (10.0 eq.) and corresponding ligand (2.2 eq.) were charged in adry reaction flask. DCM (40 mL/mmol [Ir]) was added under argon, and thereaction mixture stirred at room temperature. After completion of thereaction (conversion monitored by ¹H-NMR), the reaction mixture wasfiltered through a plug of Celite® and washed with DCM. The motherliquor was concentrated to dryness to afford the iridium-chloro-complex.For further purification procedures see detailed explanations under eachproduct.

Example 1: Preparation of (N,1,1-tris(4-methoxyphenyl)methanimineIridium Chloro Complex (VI-1)

A one-necked round bottom flask, equipped with a magnetic stirrer barand a condenser, was charged with 4-methoxyaniline (0.598 g),bis(4-methoxyphenyl)methanone (1.00 g), molecular sieves and toluene(8.0 mL), and the reaction mixture stirred at reflux for 24 h. Thereaction mixture was cooled to RT and filtered through filter paper. Theresulting filtrate was reduced under vacuum to afford N,1,1-tris(4-methoxyphenyl)methanimine.

A one-necked round bottom flask, equipped with a magnetic stirrer bar,was charged with N,1,1-tris(4-methoxyphenyl)methanimine (324 mg), DCM(4.3 mL), dichloro(pentamethylcyclopentadienyl)-iridium(III)dimer (300mg), and sodium acetate (150.0 mg), and the reaction mixture stirred atreflux for 3 h. Another portion ofN,1,1-tris(4-methoxyphenyl)methanimine (100 mg) was added and themixture was stirred for a further 30 min at reflux. The reaction mixturewas then filtered through a pad of silica and the filtrate reduced undervacuum. The resultant solid was dissolved in boiling dichloroethane (5mL), and MeOH (15 mL) was added. The mixture was left overnight in afreezer (−22° C.), and the resultant crystals were isolated bydecantation, washed with MeOH and dried under vacuum to afford 361 mg ofthe title compound (VI-1), as red crystals.

¹H NMR (CDCl₃) 5=7.38 (d, J=2.6 Hz, 1H), 6.57-7.36 (m, 9H), 6.49 (dd,J=8.4 Hz, J=2.6 Hz, 1H), 3.90 (s, 3H), 3.77 (s, 3H), 3.75 (s, 3H), 1.47(s, 15H) ppm.

TABLE 2 Iridium-chloro-complexes of formula (VI) prepared according toGeneral Procedure 2: Cpd No. Structure Comments (VI-2)

87% yield (crude product triturated with Et₂O/n-Hexane = 1:2) ¹H NMR(CDCl₃) δ 7.83 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.36 (d, J= 2.6 Hz, 1H), 6.79-6.84 (m, 1H), 6.73-6.77 (m, 1H), 6.60 (dd, J = 8.4Hz, J = 2.6 Hz, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 2.30 (s, 3H), 2.05 (s,3H), 1.46 (s, 15) ppm. ¹³C NMR (CDCl₃) δ 180.5, 168.9, 161.9, 157.3,143.3, 141.6, 131.0, 130.0, 125.3, 119.2, 114.1, 112.5, 107.7, 89.4,55.5, 55.0, 18.0, 16.8, 8.8 ppm. (VI-3)

80% yield (solid washed with Et₂O) ¹H NMR (CDCl₃) δ 7.81 (m, 1H), 7.65(bs, 1H), 7.30 (bs, 1H), 7.21 (d, J = 8.4 Hz, 1H), 6.57 (dd, J = 8.4 Hz,J = 1.5 Hz, 1H), 6.49 (bs, 1H), 3.86 (s, 3H), 1.75 (s, 15H) ppm. ¹³C NMR(CDCl₃) δ 158.2, 147.3, 137.3, 136.9, 124.4, 121.8, 111.2, 107.7, 107.7,88.1, 55.4, 9.0 ppm. (VI-4)

67% yield (crude product was purified via filtration over a pad ofsilica eluted with DCM and via trituration with Et₂O/n-pentane = 1:2) ¹HNMR (CDCl₃) δ 7.29-7.38 (m, 3H), 7.12-7.19 (m, 1H), 6.89-7.96 (m, 2H),6.43-6.51 (m, 1H), 4.20-4.30 (m, 1H), 4.10-4.18 (m, 1H), 3.85 (s, 3H),3.13-3.26 (m, 1H), 2.67- 2.81 (m, 1H), 1.46 (s, 15H) ppm. (VI-5)

47% yield (the cyclometalation reaction was done in presence of4-methoxybenzaldehyde additive (1 eq.). The crude product was purifiedby column chromatography (silica, ethyl acetate - cyclohexane gradient)followed by crystallization from dichloromethane-Et₂O-pentane) ¹H NMR(CDCl₃) δ 8.15 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.48-7.52 (m, 2H),7.35-7.37 (m, 1H), 6.86-6.92 (m, 2H), 6.59 (dd, J = 8.4 Hz, J = 2.6 Hz,1H), 3.91 (s, 3H), 3.84 (s, 3H), 1.49 (s, 15H) ppm. (VI-6)

84% yield (the crude product purified by column chromatography - silica,ethyl acetate/cyclohexane gradient and trituration using n-pentane) ¹HNMR (acetone-d6) δ 7.90 (dd, J = 7.7 Hz, J = 1 Hz, 1H), 6.88-7.61 (m,12H), 6.82 (br d, J = 7.7 Hz, 1H), 1.48 (s, 15H) ppm. (VI-7)

80% yield (the crude product was purified via trituration with diethylether/n-hexane = 1:4) ¹H NMR (CDCl₃) δ 7.57-7.23 (m, 2H), 6.95 (d, J =9.2 Hz, 2H), 6.82 (dd, J = 21.3 Hz, J = 8.1 Hz, 2H), 4.23 (m, 2H), 3.87(s, 3H), 3.81-3.66 (m, 2H), 3.45 (s, 3H), 3.05-2.83 (m, 2H), 2.78-2.61(m, 2H), 1.91-1.80 (m, 2H), 1.47 (s, 15H) ppm. (VI-8)

21% yield (the crude product purified by column chromatography onsilica, dichloromethane/methanol gradient ¹H NMR (CDCl₃) δ 7.65-7.13 (m,2H), 6.99-6.92 (m, 2H), 6.80-6.72 (m, 2H), 4.83 (d, J = 17.2 Hz, 1H),4.55 (d, J = 16.9 Hz, 1H), 3.87 (s, 3H), 3.81 (s, 3H), 3.07-2.96 (m,1H), 2.90-2.81 (m, 1H), 2.79-2.70 (m, 1H), 2.69-2.61 (m, 1H), 1.93-1.76(m, 2H), 1.47 (s, 15H) ppm. (VI-9)

82% yield (the crude product was purified via trituration with diethylether) ¹H NMR (CDCl₃) δ 7.30-7.50 (m, 2H), 6.95 (dd, J = 7.70, 1.5 Hz,2H), 6.78 (dd, J = 9.9 Hz, J = 8.07 Hz, 2H), 4.52- 4.45 (m, 1H),4.28-4.20 (m, 1H), 3.87 (s, 3H), 3.83-3.73 (m, 2H), 3.09-2.97 (m, 1H),2.94-2.83 (m, 1H), 2.79-2.60 (m, 2H), 1.96-1.76 (m, 2H), 1.46 (s, 15H)ppm.

General Procedure 3: For Synthesis of Iridium-Mesylate-Complexes ofFormula (III)

A reaction flask was charged with iridium-chloro-complex (1.0 eq.) andsilver mesylate (1.1 eq.) under argon, and the reaction flask wrappedwith aluminium foil (silver mesylate is light-sensitive). CDCl₃ (2.5mL/mmol) was added and the reaction mixture was stirred under argon for20 h. The reaction mixture was diluted with CDCl₃ and filtered through asyringe filter (0.22 μm). The filtrate was concentrated under reducedpressure to provide the iridium-mesylate-complexes. For furtherpurification procedures see detailed explanations under each product.

Example 2: Preparation of(E)-4-methoxy-N-(1-(4-methoxyphenyl)ethylidene)aniline Iridium MesylateComplex (III-1)

A reaction flask was charged with(E)-4-methoxy-N-(1-(4-methoxyphenyl)ethylidene)aniline iridium chloridecomplex (400 mg, CAS=1258964-48-5) and silver mesylate (136 mg) underargon, and the reaction flask wrapped with aluminium foil (silvermesylate is light-sensitive). CDCl₃ (2 mL) was added and the reactionmixture was stirred under argon for 20 h. The reaction mixture wasdiluted with a further portion of CDCl₃ (2 mL) and filtered through asyringe filter (0.22 μm). The filtrate was concentrated under reducedpressure to provide the title compound (III-1, 401 mg) as a yellowsolid.

¹H NMR (CDCl₃) δ 7.70 (bd, J=2.6 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 6.98(bs, 4H), 6.63 (dd, J=8.4 Hz, J=2.6 Hz, 1H), 3.94 (s, 3H), 3.86 (s, 3H),2.32 (s, 3H), 1.78 (s, 3H), 1.42 (s, 15H) ppm.

¹³C NMR (CDCl₃) δ 182.2, 168.8, 162.3, 157.8, 143.4, 142.8, 129.8,121.0, 108.5, 88.3, 55.5, 55.3, 39.1, 16.7, 8.8 ppm. Two carbon signalsnot observed due to signal broadening.

TABLE 3 Iridium-mesylate complexes of formula (III) prepared accordingto General Procedure 3: Cpd No. Structure Comments (III-2)

91% yield ¹H NMR (CDCl₃) δ 8.99 (d, J = 5.1 Hz, 1H), 8.13 (d, J = 7.3Hz, 1H), 7.73-7.87 (m, 2H), 7.69 (dd, J = 7.7 Hz, J = 1.1 Hz, 1H),7.25-7.30 (m, 1H), 7.21 (td, J = 6.4 Hz, J = 1.5 Hz, 1H), 7.11 (td, J =7.5 Hz, J = 1.1 Hz, 1H), 1.76 (bs, 3H), 1.69 (s, 15H) ppm. (III-3)

Quantitative yield ¹H NMR (CDCl₃) δ 8.93 (d, J = 5.9 Hz, 1H), 7.60-7.72(m, 4H), 7.07-7.15 (m, 1H), 6.67 (dd, J = 8.4 Hz, J = 2.6 Hz, 1H), 3.93(s, 3H), 1.82 (bs, 3H), 1.68 (s, 15H) ppm. (III-4)

98% yield ¹H NMR (CDCl₃) δ 7.93 (s, 1H), 7.87 (bs, 1H), 7.59 (bs, 1H),7.25 (d, J = 8.4 Hz, 1H), 6.60- 6.68 (m, 1H), 6.57 (bs, 1H), 3.89 (s,3H), 1.74 (s, 15H) ppm. One proton signal not observed due to signalbroadening. ¹³C NMR (CDCl₃) δ 158.3, 147.9, 139.0, 137.8, 124.5, 122.4,111.1, 108.7, 108.1, 87.5, 55.5, 39.2, 9.4 ppm. (III-5)

72% yield ¹H NMR (CDCl₃) δ 8.91 (d, J = 2.6 Hz, 1H), 7.93 (dd, J = 8.4Hz, J = 2.2 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 6.95-7.30 (bm, 4H), 3.89(s, 3H), 2.46 (s, 3H), 1.97 (s, 3H), 1.45 (s, 15H) ppm. (III-6)

Quantitative yield ¹H NMR (CDCl₃) δ 7.65 (s, 1H), 6.9-7.1 (m, 3H), 4.60(s, 3H), 3.88 (s, 3H), 3.85 (s, 3H), 2.34 (s, 3H), 1.75 (bs, 3H), 1.42(s, 15H) ppm. Signals of two protons not observed due to signalbroadening. (III-7)

Quantitative yield ¹H NMR (CDCl₃) δ 7.51 (bs, 1H), 6.96 (bd, 2H), 6.39(bs, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 1.60-2.90 (m, 9H), 1.42 (s, 15H)ppm. Signals of two protons not observed due to signal broadening.(III-8)

90% yield (crude product triturated with pentane) ¹H NMR (CDCl₃) δ7.61-7.70 (m, 1H), 7.24- 7.29 (m, 3H), 6.91-7.02 (m, 2H), 6.50-6.60 (m,1H), 4.22-4.34 (m, 1H), 3.98-4.11 (m, 1H), 3.86 (s, 3H), 3.02-3.21 (m,1H), 2.63-2.76 (m, 1H), 1.83 (s, 3H), 1.44 (s, 15H) ppm. (III-9)

84% yield (the crude product dissolved in CDCl₃ and filtered through ashort pad of silica, evaporated and recrystallized from a minimum amountof dichloromethane- pentane) ¹H NMR (CDCl₃) δ 8.20 (s, 1H), 7.72 (d, J =2.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.40-7.45 (m, 2H), 6.92-6.97 (m,2H), 6.63 (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 3.94 (s, 3H), 3.86 (s, 3H),1.87 (s, 3H), 1.47 (s, 15H) ppm. (III-10)

98% yield (the crude product was dissolved in CDCl₃ and filtered througha short pad of silica, evaporated and the solid residue triturated usingpentane) ¹H NMR (CDCl₃) δ 8.24 (d, J = 7.7 Hz, 1H), 7.43 (br d, J = 4.0Hz, 2H), 6.95-7.35 (m, 10H), 6.85 (br d, J = 7.7 Hz, 1H), 1.71 (s, 3H),1.45 (s, 15H) ppm. (III-11)

91% yield (the crude product was dissolved in CDCl₃ and filtered througha short pad of silica, evaporated and the solid residue triturated usingpentane) ¹H NMR (CDCl₃) δ 7.75 (d, J = 2.2 Hz, 1H), 6.60-7.40 (m, 9H),6.52 (dd, J = 7.6 Hz, J = 2.4 Hz, 1H), 3.93 (s, 3H), 3.78 (s, 3H), 3.76(s, 3H), 1.78 (s, 3H), 1.45 (s, 15H) ppm. (III-12)

Quantitative yield ¹H NMR (CDCl) δ 7.66 (bs, 1H), 7.40-7.64 (m, 2H),6.25-6.90 (m, 2H), 6.64 (m, 1H), 3.94 (s, 3H), 3.85 (s, 3H), 2.22 (s,3H), 2.08 (bs, 3H), 1.43 (s, 15H) ppm. Signal of three protons notobserved due to signal broadening. (III-13)

86% yield (triturated using diethylether and n- pentane) ¹H NMR (CDCl₃)δ 9.25 (d, J = 4.8 Hz, 1H), 8.36 (d, J = 7.0 Hz, 1H), 8.25 (dd, J = 7.1Hz, J = 1 Hz, 1H), 7.80-7.88 (m, 1H), 7.55-7.70 (m, 4H), 1.75 (s, 15H),1.36 (bs, 3H) ppm. (III-17)

Quantitative yield ¹H NMR (CD₃CN) δ 7.22-7.17 (m, 2H), 7.08- 7.03 (m,2H), 6.94 (d, J = 8.1 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 4.29-4.21 (m,1H), 4.17-4.11 (m, 1H), 3.87 (s, 3H), 3.79-3.74 (m, 2H), 3.38 (s, 3H),3.22-3.11 (m, 1H), 2.95-2.83 (m, 1H), 2.79-2.70 (m, 1H), 2.68-2.58 (m,1H), 2.55- 2.22 (brs, 2H), 2.47 (s, 3H), 1.74-1.60 (m, 2H), 1.49 (s,15H) ppm. (III-18)

51% yield (triturated using diethylether) ¹H NMR (CDCl₃) δ 7.73-7.11 (brm, 2H), 7.45- 6.97 (bm, 2H), 6.86-6.79 (m, 2H), 6.62 (d, J = 8.1 Hz,1H), 5.02-4.80 (bm, 1H), 4.75-4.57 (bm, 1H), 3.88 (s, 3H), 3.85 (s, 3H),2.95-2.54 (m, 4H), 1.93 (bs, 3H), 1.80-1.55 (s, 2H), 1.45 (s, 15H) ppm.(III-19)

82% yield ¹H NMR (CD₃CN) δ 7.47-7.12 (m, 2H), 7.00 (d, J = 9.2 Hz, 1H),6.84 (d, J = 8.1 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 4.82-4.70 (m, 1H),4.49-4.28 (m, 2H), 4.06-3.91 (m, 2H), 3.88 (s, 3H), 2.96-2.59 (m, 4H),1.92 (s, 3H), 1.76-1.56 (m, 2H), 1.44 (s, 15H) ppm.

Example 3: Preparation of(E)-4-methoxy-N-(1-(4-methoxyphenyl)ethylidene)aniline Iridium SulfateComplex (III-14)

A reaction vial was charged with pentamethylcyclopentadienyl iridiumsulfate complex (143 mg, CAS=[254734-81-1]),(E)-N,1-bis(4-methoxyphenyl)ethanimine (76 mg) and CD₃OD (1.2 mL) underargon. The reaction vial was stirred overnight. ¹H NMR analysis of thereaction mixture revealed formation of the cyclometalated iridiumcomplex in 73% NMR yield.

¹H NMR (CDCl₃) δ 7.65 (d, J=8.4 Hz, 1H), 7.57 (d, J=2.2 Hz, 1H), 6.77(dd, J=8.4 Hz, J=2.2 Hz, 1H), 3.94 (s, 3H), 3.87 (s, 3H), 2.42 (s, 3H),1.42 (s, 15H) ppm. Signal of four protons not observed due to signalbroadening.

Example 4: Preparation of(E)-4-methoxy-N-(1-(4-methoxyphenyl)ethylidene)aniline iridium(acetonitrile) tetrafluoroborate complex (III-15)

A reaction vial was charged with(E)-4-methoxy-N-(1-(4-methoxyphenyl)ethylidene)aniline iridium chloridecomplex (250 mg, CAS=1258964-48-5), sodium tetrafluoroborate (89 mg),and acetonitrile (1.6 mL). The reaction mixture was stirred at RT for 48h and filtered through a pad of celite (washed with DCM). The filtratewas concentrated under vacuum and the solid residue was triturated usingdiethylether providing 246 mg of the title compound as a yellow solid.

¹H NMR (CDCl₃) δ 7.52 (d, J=8.4 Hz, 1H), 7.27 (d, J=2.4 Hz, 1H),7.00-7.20 (bs, 4H), 6.72 (dd, J=8.4 Hz, J=2.4 Hz, 1H), 3.94 (s, 3H),3.88 (s, 3H), 2.60 (s, 3H), 2.42 (s, 3H), 1.49 (s, 15H) ppm.

Example 5: Preparation of(E)-4-methoxy-N-(1-(4-methoxyphenyl)ethylidene)aniline IridiumTrifluoroacetate Complex (III-16)

A reaction vial was charged with(E)-4-methoxy-N-(1-(4-methoxyphenyl)ethylidene)aniline iridium chloridecomplex (250 mg, CAS=1258964-48-5), silver trifluoroacetate (107 mg) andCDCl₃ (1.0 mL). The reaction mixture was stirred at RT for 20 h andfiltered through a pad of celite (washed with dichloromethane). Thefiltrate was concentrated and purified by column chromatography (silica,ethylacetate-cyclohexane gradient). The isolated solid was dissolved ina minimal amount of dichloromethane and diluted with n-pentane. Theproduct crystallised in a freezer overnight. The product was recoveredby decantation, washed with n-pentane and dried under vacuum to afford129 mg of the title compound as a yellow solid.

¹H NMR (CDCl₃) δ 7.66 (d, J=2.2 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H),6.09-7.10 (bm, 2H), 6.55-6.65 (m, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 2.29(s, 3H), 1.43 (s, 15H) ppm. Signals of two protons not observed due tosignal broadening.

Examples 6: Synthesis of Hydroxylamine (II-1) Via Oxime Hydrogenation

A 100 mL Hastelloy reactor was charged with(E)-N-methoxy-1-(2,4,6-trichlorophenyl)propan-2-imine (2.00 g, 99:1=E/Z,95% NMR purity) and catalyst (III-1) (5.0 mg) as a solid, the reactorwas closed and flushed with argon. iPrOH (10 mL, anhydrous, degassedwith argon) and methanesulfonic acid (0.72 mL) were added to the reactorunder argon, and the reactor was purged with hydrogen (3×5bar),pressurized to 50 bar H₂ and stirred overnight at 23° C. Hydrogen wasreleased and the reactor was again purged with argon. GC and NMRanalysis of the crude reaction mixture indicated full conversion. Thereaction mixture was added slowly onto sat. NaHCO₃ solution (15 mL) andwater (10 mL), and extracted with dichloromethane (2×15 mL). Thecombined organic layers were dried with Na₂SO₄, filtered and evaporatedto give 1.97 g (97% NMR purity) of the desired product (II-1).

Example 7: Synthesis of Hydroxylamine (II-1) Via Oxime Hydrogenation,Various Conditions

Conditions: catalyst III-1, 1.5 eq methanesulfonic acid, iPrOH solvent(200 g substrate/1 L solvent) unless otherwise indicated.

TABLE 4 Conditions and outcome of reactions according to Example 7Conditions Outcome 0.1 mol % cat., 50 bar H₂, 50° C., 2 h 100% conv.(>95% NMR yield, 2 g scale) 0.1 mol % cat., 50 bar H₂, RT, 16 h 100%conv. 0.1 mol % cat., 50 bar H₂, 10° C., 16 h 100% conv. 0.05 mol %cat., 30 bar H₂, RT, 15 h 100% conv. 0.05 mol % cat., 20 bar H₂, RT, 15h 100% conv. 0.1 mol % cat., 10 bar H₂, RT, 15 h 100% conv. 0.1 mol %cat., 50 bar H₂, RT, 100% conv. 3 equivalents of methanesulfonic acid,16 h 0.1 mol % cat., 50 bar H₂, RT,  97% conv. 1 equivalent H₂SO₄, 16 h0.1 mol % cat., 50 bar H₂, RT, 1.5  96% conv. equivalent(+)-camphorsulfonic acid, 16 h 0.01 mol % cat 50 bar H₂, RT, 91 h  76%conv. 1 mol % cat., 1.5 equivalents (+)-camphorsulfonic acid, THF, 50bar Hz, 60° C., 24 h  90% conv.

In all reactions gave high selectivity (>95%) towards the desiredproduct.

Example 8: Synthesis of Hydroxylamine (II-1) Via Oxime HydrogenationUsing Various Catalysts

Conditions: 1.5 eq methanesulfonic acid, iPrOH solvent (200 gsubstrate/1 L solvent), 0.1 mol % catalyst, 30 bar H₂, RT, 16 h, unlessotherwise indicated.

TABLE 5 Conditions and outcome of reactions according to Example 8Reaction Outcome Catalyst Time (h) (% Conversion) (III-8) 16 100 (III-9)16 99 (III-10) 16 100 0.01 mol % (III-11), 91 h 91 76 1 mol % (III-13)16 90 (III-15) 16 75 (III-16) 16 100 0.1 mol % (III-17), 3 h 3 97 0.025mol % (III-17), 3 h 3 91 0.1 mol % (III-18), 3 h 3 100 0.025 mol %(III-18), 3 h 3 95 0.1 mol % (III-19), 3 h 3 97 0.025 mol % (III-19), 3h 3 74

In all reactions high selectivity towards the desired product (>95%) wasobserved.

Example 9: Synthesis of Hydroxylamines (II) Via Oxime Hydrogenation,Substrate Scope

Conditions: 1.5 eq methanesulfonic acid, iPrOH solvent, 1 mol % catalystill-1, 50 bar H₂, RT, 16 h

TABLE 6 Hydroxylamine products (II) prepared according to Example 9: CpdNo. Structure Comments (II-2)

N-methoxy-1-(4-methoxyphenyl)ethanamine Quantitative yield ¹H NMR (400MHz, CDCl₃): δ 7.26 (d, 2H, J = 8.8 Hz), 6.86 (d, 2H, J = 8.4 Hz), 5.56(d, 1H, J = 5.1 Hz), 4.19 (q, 1H, J = 6.2 Hz), 3.79 (s, 3H), 3.47 (s,3H), 1.34 (d, 3H, J = 6.6 Hz) ppm. ¹³C NMR (400 MHz, CDCl₃): δ 158.94,134.86, 128.22, 113.81, 62.51, 59.85, 55.28, 19.84 ppm. LCMS: Mass =181, R_(t) = 4.29 (II-3)

N-benzyloxy-1-(4-methoxyphenyl)ethanamine 89% yield ¹H NMR (400 MHz,CDCl₃): δ 7.24-7.32 (m, 7H), 6.85 (d, 2H, J = 8.4 Hz), 5.56 (bs 1H),4.57-4.66 (m, 2H), 4.11 (q, 1H, J = 6.6 Hz), 3.78 (s, 3H), 1.33 (d, 3H,J = 6.6 Hz) ppm. ¹³C NMR (400 MHz, CDCl₃): δ 159.00, 137.99, 134.96,128.53, 128.41, 127.81, 113.81, 60.02, 55.32, 19.96 ppm. LCMS: Mass =258, R_(t) = 7.43 (II-4)

N-isopropoxy-1-(4-methoxyphenyl)ethanamine 90% yield ¹H NMR (400 MHz,CDCl₃): δ 7.18 (d, 2H, J = 8.4 Hz), 6.77 (d, 2H, J = 8.4 Hz), 5.20 (bs,1H), 3.97 (q, 1H, J = 6.4 Hz), 3.71 (s, 3H), 3.60-3.75 (m, 1H), 1.27 (d,3H, J = 6.5 Hz), 1.05 (d, J = 6.2 Hz, 3H), 0.96 (d, J = 6.2 Hz, 3H) ppm.(II-5)

N-tert-butoxy-1-(4-methoxyphenyl)ethanamine Quantitative yield,reaction, conducted at 50° C. ¹H NMR (400 MHz, CDCl₃): δ 7.17 (d, 2H, J= 8.4 Hz), 6.77 (d, 2H, J = 8.4 Hz), 4.78 (bs, 1H), 3.90 (q, 1H, J = 6.4Hz), 3.71 (s, 3H), 1.27 (d, 3H, J = 6.5 Hz) ppm. ¹³C NMR (400 MHz,CDCl₃): δ 158.86, 135.11, 128.58, 127.13, 113.60, 59.75, 55.24, 26.91,19.84 ppm. LCMS: Mass = 223, R_(t) = 5.32 (II-6)

N-allyloxy-1-(4-methoxyphenyl)ethanamine 49% yield, product isolated bycolumn chromatography ¹H NMR (400 MHz, CDCl₃): δ 7.23 (d, 2H, J = 8.8Hz), 6.85 (d, 2H, J = 8.4 Hz), 5.95 (ddt, 1H, J₁ = 16.8 Hz, J₂ = 10.5Hz, J₃ = 6.6 Hz), 5.11-5.15 (m, 2H), 3.78-3.83 (m, 4H), 3.26-3.31 (m,1H), 3.16 (d, 1H, J = 5.9 Hz), 1.46 (d, 3H, J = 6.6 Hz) ppm. ¹³C NMR(400 MHz, CDCl₃): δ 158.90, 134.36, 129.21, 118.35, 113.76, 65.49,59.88, 55.27, 19.53 ppm. LCMS: Mass = 207, R_(t) = 5.65 (II-7)

N-[1-(4-methoxyphenyl)ethyl]hydroxylamine 77% yield, reaction done at50° C. The product analytical data are in agreement with the literature:Org. Proc. Res. Dev. 2009, 13, 49-53. (II-8)

N-methoxy-1-(4-methoxyphenyl)methanamine 88% yield The productanalytical data are in agreement with the literature: Heterocycles 2009,78, 463-470. (II-9)

1-(3-chlorophenyl)-N-methoxy-propan-1-amine 62% yield ¹H NMR (400 MHz,CDCl₃): δ 7.33 (s, 1H), 7.19-7.25 (m, 3H), 5.68 (bs, 1H), 3.84 (bs, 1H),3.43 (s, 3H), 1.73-1.83 (m, 1H), 1.53-1.63 (m, 1H), 0.82 (t, 3H, J = 7.5Hz) ¹³C NMR (400 MHz, CDCl₃): δ 144.10, 134.19, 129.55, 127.78, 127.53,125.94, 66.90, 62.49, 26.67, 10.51 LCMS: Mass = 199, R_(t) = 4.30(II-10)

N-methoxy-1-(4-nitrophenyl)ethanamine 94% yield ¹H NMR (400 MHz, CDCl₃):δ 8.12 (d, 2H, J = 8.5 Hz), 7.47 (d, 2H, J = 8.5 Hz), 5.15 (bs, 1H),4.18 (q, 1H, J = 6.6 Hz), 3.35 (s, 3H), 1.26 (d, 3H, J = 6.6 Hz) ppm.(II-11)

N-methoxy-1-(o-tolyl)ethanamine 48% yield ¹H NMR (400 MHz, CDCl₃): δ7.33-7.38 (m, 1H), 7.05- 7.18 (m, 4H), 5.51 (bs, 1H), 4.30-4.38 (m, 1H),3.44 (s, 3H), 2.30 (s, 3H), 1.26 (d, J = 6.6 Hz, 3H) ppm. (II-12)

N-methoxy-1-(4-methoxyphenyl)propan-2-amine 80% yield ¹H NMR (400 MHz,CDCl₃): δ = 7.11 (d, 2H, J = 8.5 Hz), 6.84 (d, 2H, J = 8.5 Hz), 5.5 (bs,1H), 3.79 (s, 3H), 3.56 (s, 3H), 3.13-3.25 (m, 1H), 2.70-2.80 (m, 1H),2.50- 2.62 (m, 1H), 1.08 (d, J = 6.6 Hz, 3H) ppm. (II-13)

methyl 2-(methoxyamino)propanoate 77% yield, isolated as mesylate saltThe product analytical data are in agreement with the literature values:WO2015/052076 (II-14)

N-(2,2-dimethoxy-1-methyl-ethyl)hydroxylamine 70% yield ¹H NMR (400 MHz,CDCl₃): δ 5.90 (br s, 1H), 4.32 (d, J = 6.2 Hz, 1H), 3.54 (s, 3H), 3.44(d, J = 5.1 Hz, 6H), 3.15-3.05 (m, 1H), 1.13 (d, J = 6.6 Hz, 3H) ppm.(II-15)

N-(1-cyclopropylethyl)hydroxylamine 49% yield ¹H NMR (400 MHz, CDCl₃): δ6.39 (br s, 2H), 2.25 (dq, J = 9.2, 6.2 Hz, 1H), 1.23 (d, J = 6.6 Hz,3H), 0.81-0-7 (m, 1H), 0.56-0.46 (m, 2H), 0.35-0.25 (m, 1H), 0.22- 01.4(m, 1H) ppm. (II-16)

N-tert-butoxy-1-(4-methoxyphenyl)ethanamine 97% yield Analytical dataare in agreement with Angew. Chem. Int. Ed. 2014, 53, 13278-13281.(II-17)

N-tert-butoxy-1-(2,4,6-trichlorophenyl)propan-2-amine 90% yield ¹H NMR(400 MHz, CDCl₃): δ 7.33 (s, 2H), 4.70 (br s, 1H), 3.38-3.27 (m, 1H),3.17 (dd, J = 13.6, 6.2 Hz, 1H), 2.85 (dd, J = 13.2, 7.7 Hz, 1H), 1.15(s, 9H), 1.1 (d, J = 6.2 Hz, 3H) ppm. (II-18)

1-(2-bromophenyl)-N-methoxy-propan-2-amine 93% yield ¹H NMR (400 MHz,CDCl₃): δ 7.57 (d, J = 7.7 Hz, 1H), 7.29-7.24 (m, 2H), 7.14-7.06 (m,1H), 5.52 (br s, 1H), 3.58 (s, 3H), 3.41-3.31 (m, 1H), 3.03 (dd, J =13.2, 7.0 Hz, 1H), 2.75 (dd, J = 13.6, 7.0 Hz, 1H), 1.14 (d, J = 6.2 Hz,3H) ppm. (II-19)

N-benzyloxy-3,3-dimethyl-butan-2-amine 99% yield ¹H NMR (400 mHz,CDCl₃): δ 7.42-7.28 (m, 5H), 5.48 (br s, 1H), 4.70 (s, 2H), 2.78 (q, J =6.24 Hz, 1H), 1.20 (d, J = 6.2 Hz, 3H), 0.92 (s, 9H) ppm.

Example 10: Ionic hydrogenation of other substrates—Synthesis ofcis-N-[2-(2,4-dichlorophenyl)cyclobutyl]acetamide Via AcylenamineHydrogenation

A 50 mL glass vial was charged withN-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]acetamide (256 mg), catalyst(III-1) (6.8 mg), methanesulfonic acid (48 mg), and isopropanol (4 mL).The glass vial was placed in a parallel autoclave purged with hydrogen(3 times) and hydrogenated at 50 bar hydrogen and 23° C. for 16 h.Hydrogen was released and the reactor was purged with argon. GC and NMRanalysis of the crude reaction mixture indicated full conversion. Thereaction mixture was added slowly onto a sat. NaHCO₃ solution (15 mL)and water (10 mL), and extracted with DCM (2×15 mL). The combinedorganic layers were dried with Na₂SO₄, filtered and evaporated to give250 mg of cis N-[2-(2,4-dichlorophenyl)cyclobutyl]acetamide. Theanalytical data are in agreement with the literature: WO15/003951.

Example 11: Ionic Hydrogenation of Other Substrates—Synthesis of2-(trifluoromethyl)piperidine Via Heterocycle Hydrogenation

A 50 mL glass vial was charged with 2-trifluoromethylpyridine (144 mg),catalyst (III-1) (6.8 mg), methanesulfonic acid (144 mg) and isopropanol(4 mL). The glass vial was placed in a parallel autoclave purged withhydrogen (3 times) and hydrogenated at 50 bar hydrogen and 50° C. for 16h. Hydrogen was released and the reactor was purged with argon. GC andNMR analysis of the crude reaction mixture indicated full conversion.The reaction mixture was evaporated and analysed by NMR. Full conversionof the starting material and formation of 2-(trifluoromethyl)piperidine(CAS=154630-93-0) was found.

Comparative Example 1

Screening of 96 diverse homogeneous catalysts—metal precursors (Rh, Ir,Pt, Ru, neutral/cationic)/ligand classes (monodentate/bidentate,phosphine, phosphite, etc.) in two solvents (THF/TFA and MeOH) at T=60°C. and pressure H₂=50 bar, at a catalyst loading of 2%. The conversiontowards the desired product (II-1, labeled ‘Product’ in the table below)was determined by GC and is based on area percentages.

TABLE 7 Product Metal Precursor, Ligand Solvent (II-1) A1 Rh(COD)₂BF₄,(R)-Monophos THF/TFA 0% B1 Rh(COD)₂BF₄, (S)-Tol-Binap THF/TFA 0% C1Rh(COD)₂BF₄, (R)-DM-Segphos THF/TFA 0% D1 Rh(COD)₂BF₄, (S)-MeO-BiphepTHF/TFA 0% E1 Rh(COD)₂BF₄, (S,S,R,R)-Tangphos THF/TFA 0% F1 Rh(COD)₂BF₄,(R,S)-Binaphos THF/TFA 0% G1 Rh(COD)₂BF₄, (R,R)-Kelliphite THF/TFA 0% H1Rh(COD)₂BF₄, (R)-(+)-2-[2-diphenylphosphino)-phenyl]-4- THF/TFA 0%isopropyl-oxazoline A2 [Rh(COD)Cl]₂, (R)-Monophos THF/TFA 0% B2[Rh(COD)Cl]₂, (S)-Tol-Binap THF/TFA 0% C2 [Rh(COD)Cl]₂, (R)-DM-SegphosTHF/TFA 0% D2 [Rh(COD)Cl]₂, (S)-MeO-Biphep THF/TFA 0% E2 [Rh(COD)Cl]₂,(S,S,R,R)-Tangphos THF/TFA 0% F2 [Rh(COD)Cl]₂, (R,S)-Binaphos THF/TFA 0%G2 [Rh(COD)Cl]₂, (R,R)-Kelliphite THF/TFA 0% H2 [Rh(COD)Cl]₂,(R)-(+)-2-[2-diphenylphosphino)-phenyl]-4- THF/TFA 0%isopropyl-oxazoline A3 Ir(COD)₂BF₄, (R)-Monophos THF/TFA 0.09%   B3Ir(COD)₂BF₄, (S)-Tol-Binap THF/TFA 0% C3 Ir(COD)₂BF₄, (R)-DM-SegphosTHF/TFA 0% D3 Ir(COD)₂BF₄, (S)-MeO-Biphep THF/TFA 0% E3 Ir(COD)₂BF₄,(S,S,R,R)-Tangphos THF/TFA 0% F3 Ir(COD)₂BF₄, (R,S)-Binaphos THF/TFA 0%G3 Ir(COD)₂BF₄, (R,R)-Kelliphite THF/TFA 0% H3 Ir(COD)₂BF₄,(R)-(+)-2-[2-diphenylphosphino)-phenyl]-4- THF/TFA 0%isopropyl-oxazoline A4 [Ir(COD)Cl]₂, (R)-Monophos THF/TFA 0.02%   B4[Ir(COD)Cl]₂, (S)-Tol-Binap THF/TFA 0% C4 [Ir(COD)Cl]₂, (R)-DM-SegphosTHF/TFA 0.02%  D4 [Ir(COD)Cl]₂, (S)-MeO-Biphep THF/TFA 0.03%  E4[Ir(COD)Cl]₂, (S,S,R,R)-Tangphos THF/TFA 0% F4 [Ir(COD)Cl]₂,(R,S)-Binaphos THF/TFA 0% G4 [Ir(COD)Cl]₂, (R,R)-Kelliphite THF/TFA 0%H4 [Ir(COD)Cl]₂, (R)-(+)-2-[2-diphenylphosphino)-phenyl]-4- THF/TFA 0%isopropyl-oxazoline A5 Pt(COD)Cl₂, (R)-Monophos THF/TFA 0% B5Pt(COD)Cl₂, (S)-Tol-Binap THF/TFA 0% C5 Pt(COD)Cl₂, (R)-DM-SegphosTHF/TFA 0% D5 Pt(COD)Cl₂, (S)-MeO-Biphep THF/TFA 0% E5 Pt(COD)Cl₂,(S,S,R,R)-Tangphos THF/TFA 0% F5 Pt(COD)Cl₂, (R,S)-Binaphos THF/TFA 0%G5 Pt(COD)Cl₂, (R,R)-Kelliphite THF/TFA 0.02%   H5 Pt(COD)Cl₂,(R)-(+)-2-[2-diphenylphosphino)-phenyl]-4- THF/TFA 0%isopropyl-oxazoline A6 [Ru(cymene)Cl₂]₂, (R)-Monophos THF/TFA 0.02%  B6[Ru(cymene)Cl₂]₂, (S)-Tol-Binap THF/TFA 0% C6 [Ru(cymene)Cl₂]₂,(R)-DM-Segphos THF/TFA 0% D6 [Ru(cymene)Cl₂]₂, (S)-MeO-Biphep THF/TFA 0%E6 [Ru(cymene)Cl₂]₂, (S,S,R,R)-Tangphos THF/TFA 0% F6 [Ru(cymene)Cl₂]₂,(R,S)-Binaphos THF/TFA 0% G6 [Ru(cymene)Cl₂]₂, (R,R)-Kelliphite THF/TFA0% H6 [Ru(cymene)Cl₂]₂, (R)-(+)-2-[2-diphenylphosphino)-phenyl]-4-THF/TFA 0% isopropyl-oxazoline A7 Rh(COD)₂BF₄, (R)-Monophos MeOH 0% B7Rh(COD)₂BF₄, (S)-Tol-Binap MeOH 0% C7 Rh(COD)₂BF₄, (R)-DM-Segphos MeOH0% D7 Rh(COD)₂BF₄, (S)-MeO-Biphep MeOH 0% E7 Rh(COD)₂BF₄,(S,S,R,R)-Tangphos MeOH 0% F7 Rh(COD)₂BF₄, (R,S)-Binaphos MeOH 0% G7Rh(COD)₂BF₄, (R,R)-Kelliphite MeOH 0% H7 Rh(COD)₂BF₄,(R)-(+)-2-[2-diphenylphosphino)-phenyl]-4- MeOH 0% isopropyl-oxazolineA8 [Rh(COD)Cl]₂, (R)-Monophos MeOH 0% B8 [Rh(COD)Cl]₂, (S)-Tol-BinapMeOH 0% C8 [Rh(COD)Cl]₂, (R)-DM-Segphos MeOH 0% D8 [Rh(COD)Cl]₂,(S)-MeO-Biphep MeOH 0% E8 [Rh(COD)Cl]₂, (S,S,R,R)-Tangphos MeOH 0% F8[Rh(COD)Cl]₂, (R,S)-Binaphos MeOH 0% G8 [Rh(COD)Cl]₂, (R,R)-KelliphiteMeOH 0% H8 [Rh(COD)Cl]₂, (R)-(+)-2-[2-diphenylphosphino)-phenyl]-4- MeOH0% isopropyl-oxazoline A9 Ir(COD)₂BF₄, (R)-Monophos MeOH 0.02%  B9Ir(COD)₂BF₄, (S)-Tol-Binap MeOH 0% C9 Ir(COD)₂BF₄, (R)-DM-Segphos MeOH0% D9 Ir(COD)₂BF₄, (S)-MeO-Biphep MeOH 0% E9 Ir(COD)₂BF₄,(S,S,R,R)-Tangphos MeOH 0% F9 Ir(COD)₂BF₄, (R,S)-Binaphos MeOH 0% G9Ir(COD)₂BF₄, (R,R)-Kelliphite MeOH 0% H9 Ir(COD)₂BF₄,(R)-(+)-2-[2-diphenylphosphino)-phenyl]-4- MeOH 0% isopropyl-oxazolineA10 [Ir(COD)Cl]₂, (R)-Monophos MeOH 0.75%  B10 [Ir(COD)Cl]₂,(S)-Tol-Binap MeOH 0% C10 [Ir(COD)Cl]₂, (R)-DM-Segphos MeOH 0% D10[Ir(COD)Cl]₂, (S)-MeO-Biphep MeOH 0% E10 [Ir(COD)Cl]₂,(S,S,R,R)-Tangphos MeOH 0% F10 [Ir(COD)Cl]₂, (R,S)-Binaphos MeOH 0.05% G10 [Ir(COD)Cl]₂, (R,R)-Kelliphite MeOH 0.02%  H10 [Ir(COD)Cl]₂,(R)-(+)-2-[2-diphenylphosphino)-phenyl]-4- MeOH 0% isopropyl-oxazolineA11 Pt(COD)Cl₂, (R)-Monophos MeOH 0.02%  B11 Pt(COD)Cl₂, (S)-Tol-BinapMeOH 0.04%  C11 Pt(COD)Cl₂, (R)-DM-Segphos MeOH 0% D11 Pt(COD)Cl₂,(S)-MeO-Biphep MeOH 0% E11 Pt(COD)Cl₂, (S,S,R,R)-Tangphos MeOH 0% F11Pt(COD)Cl₂, (R,S)-Binaphos MeOH 0% G11 Pt(COD)Cl₂, (R,R)-Kelliphite MeOH0.73%  H11 Pt(COD)Cl₂, (R)-(+)-2-[2-diphenylphosphino)-phenyl]-4- MeOH0% isopropyl-oxazoline A12 [Ru(cymene)Cl₂]₂, (R)-Monophos MeOH 0% B12[Ru(cymene)Cl₂]₂, (S)-Tol-Binap MeOH 0% C12 [Ru(cymene)Cl₂]₂,(R)-DM-Segphos MeOH 0% D12 [Ru(cymene)Cl₂]₂, (S)-MeO-Biphep MeOH 0% E12[Ru(cymene)Cl₂]₂, (S,S,R,R)-Tangphos MeOH 0% F12 [Ru(cymene)Cl₂]₂,(R,S)-Binaphos MeOH 0.04%  G12 [Ru(cymene)Cl₂]₂, (R,R)-Kelliphite MeOH0% H12 [Ru(cymene)Cl₂]₂, (R)-(+)-2-[2-diphenylphosphino)-phenyl]-4- MeOH0% isopropyl-oxazoline

These experiments demonstrate that combinations of commonly used metalprecursors and ligands doesn't allow homogeneous hydrogenation of oximesubstrates such as (I-1) as in all cases, the amount of product (II-1)formed was <1%.

Comparative Example 2

Hydrogenation conditions: Temperature=60° C. and pressure H₂=60 bar,Time=20 h. Reaction conditions as described in EP1862446. The conversiontowards the desired product ((II-1), labeled ‘Product’ in the tablebelow) was determined by GC and is based on area percentages.

TABLE 8 Product Conditions (II-1)% Rh(COD)₂BF₄ (1.2 mol %), SL-J002-1*(2 mol %),    0% HBF₄•Et₂O (4 eq.), THF Rh(COD)₂BF₄ (0.12 mol %),SL-J002-1* (0.2 mol %),    0% HBF₄•Et₂O (4 eq.), THF Rh(COD)₂BF₄ (1.2mol %), SL-J002-1* (2 mol %),    0% CF₃COOH (4 eq.), CF₃CH₂OHRh(COD)₂BF₄ (0.12 mol %), SL-J002-1* (0.2 mol %),    0% CF₃COOH (4 eq.),CF₃CH₂OH Ir(COD)₂BF₄ (1.2 mol %), SL-J002-1* (2 mol %), <10% HBF₄•Et₂O(4 eq.), THF Ir(COD)₂BF₄ (0.12 mol %), SL-J002-1* (0.2 mol %), TraceHBF₄•Et₂O (4 eq.), THF (<1%) Ir(COD)₂BF₄ (1.2 mol %), SL-J002-1* (2 mol%),    0% CF₃COOH (4 eq.), CF₃CH₂OH Ir(COD)₂BF₄ (0.12 mol %), SL-J002-1*(0.2 mol %),    0% CF₃COOH (4 eq.), CF₃CH₂OH *SL-J002-1 =(R)-1-[(SP)-2-(Diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine

In all cases, low selectivity and no or very low yield of the desiredproduct (II-1, labeled ‘Product’ in the table above) was observed. Theseexperiments demonstrate that the catalysts and conditions described inEP 1862446 A2 do not allow efficient hydrogenation of oxime substratessuch as (II-1).

Comparative Example 3

No formation of the desired product (II-1) was observed under reactionconditions as described in Org. Biomol. Chem., 2013, 11, 6934.

Comparative Example 4

Conversion Product Conditions % (II-1)% Catalyst 0.5 mol %, 0% 0%Solvent = THF, 50° C. Catalyst 0.1 mol %, 0% 0% Solvent = iPrOH, RT

No formation of the desired product (II-1) was observed under reactionconditions as described in our invention, but using an iridium chlorocomplex (VI) (as reported for example in Org. Biomol. Chem., 2013, 11,6934; WO 2013/153407). These experiments demonstrate that iridiumhalogen complexes are not efficient as catalysts in the current process.

Comparative Example 5

When utilizing the reaction conditions of the present invention withoutacid, the formation of the desired product (II-1) was not observed. Thisexperiment demonstrates that a stoichiometric amount of a suitable acidis essential in the process according our invention.

1. A process for the hydrogenation of an oxime of formula (I) to producea hydroxylamine salt of formula (II) by reacting oxime (I) with hydrogenin the presence of an iridium catalyst of formula (IIIa) or formula(IIIb) and an acid;

wherein R¹, R² and R³ are each independently hydrogen, C₁-C₈alkyl,C₁-C₈hydroxyalkyl, C₁-C₈cyanoalkyl, C₁-C₆alkoxyC₁-C₈alkyl,di(C₁-C₆alkoxy)C₁-C₈alkyl, C₁-C₈haloalkyl, C₂-C₆alkenyl,C₃-C₈cycloalkyl, phenyl, phenylC₁-C₃alkyl or heteroaryl, and wherein thecycloalkyl and phenyl moieties are each optionally substituted with 1 to5 groups selected from hydroxyl, halogen, C₁-C₆alkyl, C₃-C₈cycloalkyl,C₁-C₆haloalkyl, C₁-C₆alkoxy, phenyl, heteroaryl, C₁-C₆alkoxycarbonyl,acylamino, amido, cyano, nitro and C₂-C₆alkenyl; or R¹ and R² togetherwith the carbon atom to which they are attached may form a 4- to8-membered saturated cycloalkyl or heterocyclyl ring, wherein theheterocyclic moiety is a non-aromatic monocyclic ring which comprises 1,2 or 3 heteroatoms, wherein the heteroatoms are individually selectedfrom N, O and S; R⁶, R⁷, R⁸, R⁹ and R¹⁰ are each independently hydrogenor C₁-C₃alkyl;

represents a bidentate chelating ligand comprising at least one carbonatom which coordinates to iridium and at least one nitrogen atom whichcoordinates to iridium; X represents an anionic group of the formulaR¹⁴—SO₂O— or R¹⁵—C(O)O—, wherein R¹⁴ is hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆haloalkyl, or phenyl, wherein the phenyl moieties are optionallysubstituted by 1, 2, 3 or 4 substituents, which may be the same ordifferent, selected from R¹⁶; R¹⁶ is C₁₋₄alkyl, C₁₋₄haloalkyl, nitro, orhalogen; R¹⁵ is C₁₋₆haloalkyl or phenyl, wherein the phenyl moieties areoptionally substituted by 1, 2, 3 or 4 substituents, which may be thesame or different, selected from R¹⁷; R¹⁷ is C₁₋₄alkyl, C₁₋₄haloalkyl,nitro or halogen; Y represents a neutral ligand; and Z represents ananionic group.
 2. The process according to claim 1, wherein R⁶, R⁷, R⁸,R⁹ and R¹⁰ each represent hydrogen or methyl.
 3. The process accordingto claim 1 or claim 2, wherein X represents a group of the formulaR¹⁴—SO₂O⁻.
 4. The process according to claim 1, wherein the bidentatechelating ligand is selected from a compound of formula (IV-1), (IV-2),(IV-3), (IV-5), (IV-6), (IV-7), (IV-8), (IV-9), (IV-10), (IV-11) and(IV-12):


5. The process according to claim 1, wherein Z is R¹⁴—SO₂O⁻, mesylate,sulfate, hydrogenosulfate, tetrafluoroborate, hexafluorophosphate,tetraphenylborate, or tetrakis(3,5-bis(trifluoromethyl)phenyl)borate. 6.The process according to claim 1, wherein the acid is methanesulfonicacid, p-toluenesulfonic acid, camphorsulfonic acid, sulfuric acid ortriflic acid.
 7. The process according to claim 1, wherein Y is H₂O orMeCN.
 8. The process according to claim 1, wherein the iridium catalystis a compound of formula (III-1), (III-11), (III-17), (III-18), or(III-19):


9. The process according to claim 1, wherein the hydroxylamine offormula (II) is N-methoxy-1-(2,4,6-trichlorophenyl)propan-2-amine(II-1).
 10. The process according to claim 9, whereinN-methoxy-1-(2,4,6-trichlorophenyl)propan-2-amine (II-1) is furtherreacted with 3-(difluoromethyl)-1-methyl-pyrazole-4-carbonyl chloride(XII) to provide3-(difluoromethyl)-N-methoxy-1-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)ethyl]pyrazole-4-carboxamide(XIII):


11. A compound of formula (IIIc) or (IIId):

wherein R⁶, R⁷, R⁸, R⁹ and R¹⁰ are each independently selected fromhydrogen or C₁-C₃alkyl; R^(11A), R^(11B), R^(11C), R^(11D), R^(11E),R^(13A), R^(13B), R^(13C), and R^(13D) are each independently hydrogen,halogen, C₁-C₈alkyl, C₁-C₈alkoxy, C₁-C₈haloalkyl, C₁-C₈haloalkoxy,hydroxyC₁-C₈alkoxy, C₁-C₈alkoxyC₁-C₆alkoxy, C₁-C₈alkoxycarbonyl,C₁-C₈alkoxycarbonylC₁-C₆alkoxy, C₁-C₈alkylcarbonylC₁-C₆alkoxy, phenoxy,or nitro; R¹² is hydrogen, C₁-C₈ alkyl or phenyl, wherein each phenylmoiety is optionally substituted by 1 to 5 groups selected fromC₁-C₈alkyl and C₁-C₈alkoxy; or R¹² and R^(13D) together with the carbonatoms to which they are attached may form a 6- to 8-membered partiallysaturated cycloalkyl or heterocyclyl ring, wherein the heterocyclicmoiety is a non-aromatic ring which comprises 1 or 2 heteroatoms,wherein the heteroatoms are individually selected from N, O and S; X ismesylate, tosylate, nosylate, sulfate, hydrogenosulfate, triflate ortrifluoroacetate; Y is H₂O, PhCN or MeCN; and Z is mesylate, tosylate,nosylate, sulfate, hydrogenosulfate, triflate, tetrafluoroborate,hexafluorophosphate, tetraphenylborate ortetrakis(3,5-bis(trifluoromethyl)phenyl)borate.
 12. The compound ofclaim 11, wherein the compound is a compound of formula (III-1),(III-11), (III-17), (III-18), and (III-19):


13. A process for ionic hydrogenation of acylenamines, imines, enamines,heterocycles, aldehydes and ketones with hydrogen in the presence of aniridium catalyst of formula (IIIa) or formula (IIIb) of claim 1 andoptionally an acid.